1 ABSTRACT 2 Human leukocyte antigens (HLA) class I, expressed on the surface of almost all cells, and killer cell 3 immunoglobulin-like receptors (KIR) expressed by natural killer cells (NK cells) are critical facets of the human 4 immune system. Variations in the KIR and HLA genes are linked directly to NK cell functions and associated 5 with many aspects of human health, including associations with pregnancy syndromes, susceptibility to 6 infectious disease, and risk of autoimmunity. Our ability to develop personalized medicine approaches such as 7 immunotherapies, to understand the mechanisms of immune mediated disease and to match organ donors 8 with recipients relies on our ability to accurately characterize KIR and HLA class I diversity. Despite this crucial 9 importance to human health, there is a deficit of knowledge concerning much of the human population. One of 10 the most neglected geographical areas in this regard is the eastern hemisphere, encompassing almost half the 11 world's population. During this project we will fill these gaps in knowledge through determining the extent and 12 functional consequences of KIR and HLA class I diversity across the entire eastern hemisphere. 13 We will examine a total of 14,250 individuals representing 51 discrete populations, including indigenous 14 populations from East Asia, South Asia, multiple Pacific islands and Oceania. To overcome difficulties in 15 analyzing the complex genomic regions, we developed a targeted sequencing and bioinformatics approach to 16 analyze KIR and HLA class I genes at high throughput and resolution. To maximize data available to us for this 17 study we will develop an imputation algorithm to determine high-resolution KIR alleles from whole-genome 18 SNP data. This goal will be made possible through the extensive training data generated. We will then 19 characterize the geographic distribution of KIR and HLA haplotypes across this region. 20 We will examine how the geographic patterns of KIR and HLA diversity have been shaped by natural selection 21 and investigate the impact of adaptive introgression and admixture specifically focused to the KIR and HLA loci 22 in our study populations. Finally, we will determine the function and avidity for cognate ligands of those variants 23 targeted by natural selection in multiple populations. We will pursue these aims implementing innovative bench 24 and analytical tools. These include the further refinement of HLA and KIR sequencing techniques, the 25 construction of an imputation panel in populations in which it is currently lacking, and the calibration of tools to 26 robustly identify balancing selection. The expected outcome of this work is the genetic and functional 27 characterization of HLA and KIR in neglected populations, a description of how this variation is geographically 28 distributed, and a more comprehensive understanding of how this was shaped by natural selection. This work 29 will significantly enhance understanding of genetically determined human immune diversity and improve 30 resolution to identify associations between this critical facet of the immune system and the many aspects of 31 human health that they impact. 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52